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Towards an Understanding of Inflammation in Macrophages /

  • Author(s): Zhang, Dawn Xiaobin
  • et al.

This dissertation utilizes in vivo and genome-wide approaches to investigate the roles of NCoR, Rev-Erb, and Coro2A in regulating transcription in a signal-dependent manner. Chapter 1 will review our current understanding of transcriptional regulation in mammalian cells, especially how certain cell-specific enhancers and genes are selected for transcription. Chapter 2 will characterize the new and unexpected role of Rev-Erbs in regulating signal-dependent enhancers during wound healing. Unexpectedly, we found that loss of Rev-Erbs in hematopoietic cells results in accelerated wound healing. Our studies suggest that Rev- Erbs regulate a broad range of enhancers vital for wound healing and that these enhancers are neither pro- inflammatory nor anti-inflammatory. Instead, the ability of Rev-Erbs to select for a subset of "wound healing" enhancers results in the fine-tuning of macrophage- mediated responses to damaged tissue. Chapter 3 describes the generation and analysis of a Coro2A total knock-out mouse. In this chapter, we utilize a genome-wide approach to investigate the role of Coro2A, a novel member of the NCoR complex, in mediating transcriptional regulation. Furthermore, our studies show that Coro2A and NCoR cooperate to regulate the expression of lipid biosynthetic and immune response genes. Finally, Chapter 4 will discuss the broader implications of this research as a whole

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